From inflammation to remodelling: A novel BASP1⁺ monocyte subset as a catalyst for acute aortic dissection

Monocytes comprise heterogeneous cell populations. However, beyond traditionally considered as precursors of tissue macrophages, heterogeneity and detailed effects of monocytes in acute aortic dissection (AAD) are largely unknown.

To investigate the role of brain soluble acid protein 1 positive (BASP1⁺) monocyte subset in promoting AAD development as well as the underlying mechanism.

Monocyte/macrophage heterogeneity in both human peripheral blood and aortic tissues were assayed by scRNA-seq. Monocyte trafficking and lineage tracing were detected by immunofluorescence and using BASP1-CreER/Lyz2-DreER-tdT reporter mice with AAD. The effects and underlying mechanism were investigated by laser speckle image, ultrasound imaging, Co-IP, ChIP-sequencing. Conditional knockout of BASP1 on monocyte and BASP1 siRNA were used to observe BASP1⁺ monocyte subset-targeted AAD intervention.

"PIP2-SP1-ACTN1/VAV3" and "ITGB1-Rac1-GSN" signalling mediated BASP1⁺ monocyte subset as the first line immune cells infiltrating aortic tissues in AAD induction and partial of them transformed to BASP1⁺ macrophages to amplify the inflammation. Meanwhile, BASP1⁺ monocyte subset induced an inflammatory phenotype vascular smooth muscle cell (VSMC) subset and a ROS-enriched endothelial cell (EC) subset accompanied with promoting the apoptosis of normal VSMC and EC, contributing to vascular remodelling and dampening the myo-endothelial gap junction. Selective deletion of BASP1⁺ monocyte subset and interference with BASP1 expression in monocytes both inhibited the development of AAD in mice.

Interpretation BASP1⁺ monocyte subset and its regulatory network provides deep insight into AAD pathogenesis and a novel potential target for early intervention in AAD formation.